The general morphological and functional derangement of hypertensive cardiac hypertrophy (HCH) are defined, both in humans and in experimental animals, and biochemical investigations at the subcellular level have brought to light an almost confusing number of abnormalities. Since the natural history of HCH is one of eventual deterioration of contractility, we propose to examine the possibility that the functional decline stems from an abnormality or limiting factor in myocardial energy metabolism. The purpose of this project is to assess in sequence functional and metabolic alterations concomitant with early, stable and advanced HCH in the one-kidney-one-clip hypertensive rabbit model. Recovery will also be assessed in hearts from animals whose pressure is normalized by nifedipine. Intrinsic cardiac performance will be determined during each stage of hypertrophy by measuring pressure-volume relationships in a flexible perfusion system of the isolated working heart. Immediately thereafter, the effects of work load on fuel selection and external efficiency at each stage of HCH and regression will be measured. To achieve this goal cardiac work will be recorded together with oxygen consumption and the rate of substrate utilization (uptake of glucose and oleate). Our primary hypothesis is that, as energy requirements increase, there is a need for the provision of citric acid cyle intermediates which may become limiting in situations of high cardiac stress. Thus, the role of glucose in providing citric acid cycle intermedates for energy production in normal and overloaded heart will be studied. In order to identify potential regulatory sites of intermediary metabolism, key metabolites will be measured in freeze-clamped hearts during an acute increase in work load. Because in skeletal muscle the purine nucleotide cycle is thought to be a major source of citric acid cycle intermediates during increased work, the activity of this pathway will be assessed by measuring release of ammonia into the perfusate and by determining key tissue metabolites during acute work stress. Lastly, oxidation of the amino acid leucine by hypertrophied heart will be measured, because leucine is not only an energy-providing substrate for the normal heart, but also acts as a signal for protein turnover. One hypothesis is that leucine oxidation is decreased in hypertrophied heart due to decreased transminase activity. The overall importance of these studies is to provide a metabolic basis for abnormal cardiac function at defined stages of HCH.